Inhibition of glutamate transporter by theanine enhances the therapeutic efficacy of doxorubicin

Theanine, a major amino acid existing in green tea, enhanced the antitumor activity of doxorubicin (DOX) due to inhibition of DOX efflux from tumor ce lls. In order to clarify the mechanism, we have investigated the contributi on of glutamate transporters to the action of theanine, because theanine is a glutamate analogue. In M5076 ovarian sarcoma cells, glutamate transport inhibitors reduced the efflux of DOX, as well as theanine. Incidentally, th eanine significantly inhibited the glutamate uptake by M5076 cells in a con centration-dependent manner similar to specific inhibitors. These results s uggested that the inhibition of DOX efflux was induced by the inhibition of glutamate transport by theanine. In addition, RT-PCR and Western blot anal ysis revealed the expression of CLAST and GLT-1, astrocytic high-affinity g lutamate transporters, in M5076 cells. Thus, theanine was shown to competit ively inhibit the glutamate uptake by acting on these glutamate transporter s. This action suggested the contribution of glutamate transporters to the inhibition of DOX efflux by theanine. We revealed the novel mechanism of en hancement of the antitumor efficacy of DOX via the inhibition of glutamate transporters by theanine. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.